14 results on '"Edwige Belotti"'
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2. Cryptic amyloidogenic elements in mutant NEFH causing Charcot-Marie-Tooth 2 trigger aggresome formation and neuronal death
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Arnaud Jacquier, Cécile Delorme, Edwige Belotti, Raoul Juntas-Morales, Guilhem Solé, Odile Dubourg, Marianne Giroux, Claude-Alain Maurage, Valérie Castellani, Adriana Rebelo, Alexander Abrams, Stephan Züchner, Tanya Stojkovic, Laurent Schaeffer, and Philippe Latour
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Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Neurofilament heavy chain (NEFH) gene was recently identified to cause autosomal dominant axonal Charcot-Marie-Tooth disease (CMT2cc). However, the clinical spectrum of this condition and the physio-pathological pathway remain to be delineated. We report 12 patients from two French families with axonal dominantly inherited form of CMT caused by two new mutations in the NEFH gene. A remarkable feature was the early involvement of proximal muscles of the lower limbs associated with pyramidal signs in some patients. Nerve conduction velocity studies indicated a predominantly motor axonal neuropathy. Unique deletions of two nucleotides causing frameshifts near the end of the NEFH coding sequence were identified: in family 1, c.3008_3009del (p.Lys1003Argfs*59), and in family 2 c.3043_3044del (p.Lys1015Glyfs*47). Both frameshifts lead to 40 additional amino acids translation encoding a cryptic amyloidogenic element. Consistently, we show that these mutations cause protein aggregation which are recognised by the autophagic pathway in motoneurons and triggered caspase 3 activation leading to apoptosis in neuroblastoma cells. Using electroporation of chick embryo spinal cord, we confirm that NEFH mutants form aggregates in vivo and trigger apoptosis of spinal cord neurons. Thus, our results provide a physiological explanation for the overlap between CMT and amyotrophic lateral sclerosis (ALS) clinical features in affected patients.
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- 2017
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3. Identification of p62/SQSTM1 as a component of non-canonical Wnt VANGL2–JNK signalling in breast cancer
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Tania M. Puvirajesinghe, François Bertucci, Ashish Jain, Pierluigi Scerbo, Edwige Belotti, Stéphane Audebert, Michael Sebbagh, Marc Lopez, Andreas Brech, Pascal Finetti, Emmanuelle Charafe-Jauffret, Max Chaffanet, Rémy Castellano, Audrey Restouin, Sylvie Marchetto, Yves Collette, Anthony Gonçalvès, Ian Macara, Daniel Birnbaum, Laurent Kodjabachian, Terje Johansen, and Jean-Paul Borg
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Science - Abstract
Defects in non-canonical Wnt/planar cell polarity signalling have recently been linked to breast cancer aggressiveness. Puvirajesinghe et al. identify VANGL2, p62/SQSTM1 and JNK as important players in this pathway which may be amenable to therapeutic intervention in breast cancer.
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- 2016
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4. Molecular characterisation of endogenous Vangl2/Vangl1 heteromeric protein complexes.
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Edwige Belotti, Tania M Puvirajesinghe, Stéphane Audebert, Emilie Baudelet, Luc Camoin, Michel Pierres, Lea Lasvaux, Géraldine Ferracci, Mireille Montcouquiol, and Jean-Paul Borg
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Medicine ,Science - Abstract
BackgroundMutations in the Planar Cell Polarity (PCP) core gene Vangl2 cause the most severe neural tube defects (NTD) in mice and humans. Genetic studies show that the Vangl2 gene genetically interacts with a close homologue Vangl1. How precisely Vangl2 and Vangl1 proteins interact and crosstalk has remained a difficult issue to address, with the main obstacle being the accurate discrimination of the two proteins, which share close sequence homology. Experimental evidence previously presented has been sparse and addressed with ectopically expressed proteins or with antibodies unable to biochemically discriminate Vangl1 from Vangl2, therefore giving rise to unclear results.Methodology and main findingsA highly specific monoclonal anti-Vangl2 antibody was generated and rigorously tested on both recombinant and extracted Vangl2 using surface plasmon resonance (SPR) analysis, western blot, and immunoprecipitation experiments. This antibody efficiently affinity-purified Vangl2 from cell lysates and allowed the unambiguous identification of endogenous Vangl2 by proteomic analysis. Vangl1 was also present in Vangl2 immunoprecipitates, establishing the first biochemical evidence for the existence of Vangl2/Vangl1 heterodimers at an endogenous level. Epitope-tagged Vangl2 and Vangl1 confirmed that both proteins interact and colocalize at the plasma membrane. The Vangl2 antibody is able to acutely assess differential expression levels of Vangl2 protein in culture cell lines, as corroborated with gene expression analysis. We characterised Vangl2 expression in the cochlea of homozygous and heterozygous Lp mutant mice bearing a point mutation within the C-terminal Vangl2 region that leads to profound PCP defects. Our antibody could detect much lower levels of Vangl2(Lp) protein in mutant mice compared to the wild type mice.ConclusionOur results provide an in-depth biochemical characterisation of the interaction observed between Vangl paralogues.
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- 2012
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5. Regulation of Gene expression at the neuromuscular Junction
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Edwige Belotti, Laurent Schaeffer, Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), CCSD, Accord Elsevier, and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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0301 basic medicine ,Regulation of gene expression ,Agrin ,General Neuroscience ,[SDV]Life Sciences [q-bio] ,Response element ,Neuromuscular Junction ,Promoter ,Biology ,Neuromuscular junction ,Chromatin ,Cell biology ,[SDV] Life Sciences [q-bio] ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,Gene Expression Regulation ,Synapses ,Gene expression ,medicine ,Transcriptional regulation ,Animals ,Humans ,030217 neurology & neurosurgery - Abstract
Gene expression in skeletal muscle is profoundly changed upon innervation. 50 years of research on the neuromuscular system have greatly increased our understanding of the mechanisms underlying these changes. By controlling the expression and the activity of key transcription factors, nerve-evoked electrical activity in the muscle fiber positively and negatively regulates the expression of hundreds of genes. Innervation also compartmentalizes gene expression into synaptic and extra-synaptic regions of muscle fibers. In addition, electrically-evoked, release of several factors (e.g. Agrin, Neuregulin, Wnt ligands) induce the clustering of synaptic proteins and of a few muscle nuclei. The sub-synaptic nuclei acquire a particular chromatin organization and develop a specific gene expression program dedicated to building and maintaining a functional neuromuscular synapse. Deciphering synapse-specific, transcriptional regulation started with the identification of the N-box, a six base pair element present in the promoters of the acetylcholine δ and ε subunits. Most genes with synapse-specific expression turned out to contain at least one N-box in their promoters. The N-box is a response element for the synaptic signals Agrin and Neuregulins as well as a binding site for transcription factors of the Ets family. The Ets transcription factors GABP and Erm are implicated in the activation of post-synaptic genes via the N-box. In muscle fibers, Erm expression is restricted to the NMJ whereas GABP is expressed in all muscle nuclei but phosphorylated and activated by the JNK and ERK signaling pathways in response to Agrin and Neuregulins. Post-synaptic gene expression also correlates with chromatin modifications at the genomic level as evidenced by the strong enrichment of decondensed chromatin and acetylated histones in sub-synaptic nuclei. Here we discuss these transcriptional pathways for synaptic specialization at NMJs.
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- 2020
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6. H2A.Z is dispensable for both basal and activated transcription in post-mitotic mouse muscles
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Kiran Padmanabhan, Ali Hamiche, Stefan Dimitrov, Lorrie Ramos, Christophe Papin, Defne Dalkara, Yann-Gaël Gangloff, Nicolas Lacoste, Isabella Scionti, Laurent Schaeffer, Edwige Belotti, Thomas Simonet, Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Inflammasome NLRP3 – NLRP3 Inflammasome, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir] (DEÜ), Hospices Civils de Lyon (HCL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), ANR-16-CE12-0013,EpiVarZ,Analyses intégratives du variant d'histone H2A.Z au niveau moléculaire, fonctionnel et structural(2016), ANR-18-CE12-0010,ZFun,Fonctions biologiques de l'histone variant H2A.Z(2018), ANR-17-CE11-0019,Chrom3D,Le rôle de l'histone H1 et de CENP-C dans la structure et les propriétés épigénétiques de la chromatine(2017), GANGLOFF, Yann-Gaël, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL)
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Transcriptional Activation ,Transcription, Genetic ,AcademicSubjects/SCI00010 ,[SDV]Life Sciences [q-bio] ,Cellular differentiation ,Muscle Fibers, Skeletal ,NAR Breakthrough Article ,Histones ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Transcription (biology) ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Genetics ,Animals ,Nucleosome ,RNA-Seq ,Muscle, Skeletal ,Mitosis ,Cells, Cultured ,Repetitive Sequences, Nucleic Acid ,030304 developmental biology ,0303 health sciences ,biology ,Cell Differentiation ,Promoter ,Cell cycle ,Chromatin ,Cell biology ,[SDV] Life Sciences [q-bio] ,Histone ,biology.protein ,Chromatin Immunoprecipitation Sequencing ,Transcription Initiation Site ,030217 neurology & neurosurgery - Abstract
While the histone variant H2A.Z is known to be required for mitosis, it is also enriched in nucleosomes surrounding the transcription start site of active promoters, implicating H2A.Z in transcription. However, evidence obtained so far mainly rely on correlational data generated in actively dividing cells. We have exploited a paradigm in which transcription is uncoupled from the cell cycle by developing an in vivo system to inactivate H2A.Z in terminally differentiated post-mitotic muscle cells. ChIP-seq, RNA-seq and ATAC-seq experiments performed on H2A.Z KO post-mitotic muscle cells show that this histone variant is neither required to maintain nor to activate transcription. Altogether, this study provides in vivo evidence that in the absence of mitosis H2A.Z is dispensable for transcription and that the enrichment of H2A.Z on active promoters is a marker but not an active driver of transcription.
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- 2020
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7. H2A.Z is dispensable for both basal and activated transcription in post-mitotic mouse muscles
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Thomas Simonet, Kiran Padmanabhan, Defne Dalkara, Ali Hamiche, Stefan Dimitrov, Nicolas Lacoste, Laurent Schaeffer, Edwige Belotti, Isabella Scionti, Lorrie Ramos, and Christophe Papin
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0303 health sciences ,biology ,Promoter ,Cell cycle ,Cell biology ,03 medical and health sciences ,0302 clinical medicine ,Histone ,In vivo ,Transcription (biology) ,biology.protein ,Nucleosome ,Myocyte ,Mitosis ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
The histone variant H2A.Z is enriched in nucleosomes surrounding the transcription start site of active promoters, suggesting that it might be implicated in transcription. It is also required during mitosis. However, evidences obtained so far mainly rely on correlative evidences obtained in actively dividing cells. We have defined a paradigm in which cell cycle cannot interfere with H2A.Z transcriptional studies by developing an in vivo systems to invalidate H2A.Z in terminally differentiated post-mitotic muscle cells to dissociate its role during transcription from its role during mitosis. ChIP-seq, RNA-seq and ATAC-seq experiments performed on H2A.Z KO post-mitotic muscle cells show that this histone variant is neither required to maintain nor to activate transcription. Altogether, this study provides in vivo evidence that in the absence of mitosis H2A.Z is dispensable for transcription and that the enrichment of H2A.Z on active promoters is rather a marker than an actor of transcriptional activity.
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- 2019
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8. mTOR inactivation in myocardium from infant mice rapidly leads to dilated cardiomyopathy due to translation defects and p53/JNK-mediated apoptosis
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Geoffrey Teixeira, Emilie Delaune, Qing Zhang, Théophile Ohlmann, Daniel Taillandier, Laetitia Mazelin, Michel Ovize, Anne-Sophie Nicot, Baptiste Panthu, Yann-Gaël Gangloff, Geneviève Derumeaux, Lionel A. Tintignac, Laurent Schaeffer, Edwige Belotti, Dominique Baas, Valérie Risson, Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Contrôle traductionnel des ARNm eucaryotes et viraux – Translational control of Eukaryotic and Viral RNAs, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Dynamique Musculaire et Métabolisme (DMEM), Institut National de la Recherche Agronomique (INRA)-Université de Montpellier (UM), Departments of Neurology and Biomedicine, Neuromuscular Research Center, Basel University Hospital, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), Service d'Anatomie et Cytologie Pathologiques, CHU Amiens-Picardie, Apoptose Cancer et Développement, Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), CINTRA / SEEE Nanyang Technological University, Nanyang Technological University [Singapour], Laboratoire de Biologie Moléculaire de la Cellule (LBMC), Service de Cardiologie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Virologie humaine, École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), UMR 5310, U1217, Institut NeuroMyoGene, Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), University Hospital Basel [Basel], Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Unité de Nutrition Humaine (UNH), Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Centre International de Recherche en Infectiologie (CIRI), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université de Montpellier (UM)-Institut National de la Recherche Agronomique (INRA)
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0301 basic medicine ,MST1 ,Biopsy ,[SDV]Life Sciences [q-bio] ,Muscle Proteins ,translation ,Apoptosis ,mTORC1 ,mTORC2 ,myocardial metabolism ,Mice ,0302 clinical medicine ,ComputingMilieux_MISCELLANEOUS ,Mice, Knockout ,Cardiopulmonary Bypass ,biology ,Myoglobin ,TOR Serine-Threonine Kinases ,Nuclear Proteins ,Cell biology ,Echocardiography ,030220 oncology & carcinogenesis ,Heart Function Tests ,mTOR ,Cardiology and Cardiovascular Medicine ,signal transduction ,Cardiomyopathy, Dilated ,medicine.medical_specialty ,ANKRD1 ,heart postnatal development ,03 medical and health sciences ,Internal medicine ,medicine ,Animals ,Molecular Biology ,Mechanistic target of rapamycin ,PI3K/AKT/mTOR pathway ,Cell growth ,Gene Expression Profiling ,RPTOR ,JNK Mitogen-Activated Protein Kinases ,cardiomyocyte apoptosis ,Repressor Proteins ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Gene Expression Regulation ,Protein Biosynthesis ,Proteolysis ,biology.protein ,Tumor Suppressor Protein p53 ,Energy Metabolism ,[SDV.AEN]Life Sciences [q-bio]/Food and Nutrition ,Biomarkers - Abstract
Mechanistic target of rapamycin (mTOR) is a central regulator of cell growth, proliferation, survival and metabolism, as part of mTOR complex 1 (mTORC1) and mTORC2. While partial inhibition of mTORC1 using rapamycin was shown to be cardioprotective, genetic studies in mouse models revealed that mTOR is essential for embryonic heart development and cardiac function in adults. However, the physiological role of mTOR during postnatal cardiac maturation is not fully elucidated. We have therefore generated a mouse model in which cardiac mTOR was inactivated at an early postnatal stage. Mutant mTORcmKO mice rapidly developed a dilated cardiomyopathy associated with cardiomyocyte growth defects, apoptosis and fibrosis, and died during their third week. Here, we show that reduced cardiomyocyte growth results from impaired protein translation efficiency through both 4E-BP1-dependent and -independent mechanisms. In addition, infant mTORcmKO hearts displayed markedly increased apoptosis linked to stretch-induced ANKRD1 (Ankyrin repeat-domain containing protein 1) up-regulation, JNK kinase activation and p53 accumulation. Pharmacological inhibition of p53 with pifithrin-α attenuated caspase-3 activation. Cardiomyocyte death did not result from activation of the MST1/Hippo pro-apoptotic pathway as reported in adult rictor/mTORC2 KO hearts. As well, mTORcmKO hearts showed a strong downregulation of myoglobin content, thereby leading to a hypoxic environment. Nevertheless, they lacked a HIF1α-mediated adaptive response, as mTOR is required for hypoxia-induced HIF-1α activation. Altogether, our results demonstrate that mTOR is critically required for cardiomyocyte growth, viability and oxygen supply in early postnatal myocardium and provide insight into the molecular mechanisms involved in apoptosis of mTOR-depleted cardiomyocytes.
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- 2016
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9. Identification of p62/SQSTM1 as a component of non-canonical Wnt VANGL2–JNK signalling in breast cancer
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Michael Sebbagh, Anthony Gonçalves, Yves Collette, Ashish Jain, Max Chaffanet, Laurent Kodjabachian, Marc Lopez, Andreas Brech, Sylvie Marchetto, Jean-Paul Borg, Audrey Restouin, Pierluigi Scerbo, Terje Johansen, Daniel Birnbaum, Stéphane Audebert, Pascal Finetti, Edwige Belotti, Tania M. Puvirajesinghe, Emmanuelle Charafe-Jauffret, François Bertucci, Rémy Castellano, Ian G. Macara, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU), Centre de recherches insulaires et observatoire de l'environnement (CRIOBE), Université de Perpignan Via Domitia (UPVD)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), The Arctic University of Norway [Tromsø, Norway] (UiT), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), Universidad de Castilla-La Mancha = University of Castilla-La Mancha (UCLM), Departamento de Química Física, Facultad de Ciencias Quimicas, Department of Biochemistry, Norwegian Radium Hospital, Cancérologie (Inserm U599/IPC), Université de la Méditerranée - Aix-Marseille 2-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Virginia, Puvirajesinghe, Puvirajesinghe, Université de Perpignan Via Domitia (UPVD)-École Pratique des Hautes Études (EPHE), The Arctic University of Norway, Universidad de Castilla-La Mancha (UCLM), and University of Virginia [Charlottesville]
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0301 basic medicine ,Embryo, Nonmammalian ,Xenopus ,General Physics and Astronomy ,[SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB] ,Mass Spectrometry ,Mice ,Cell Movement ,Cell polarity ,Sequestosome-1 Protein ,[SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB] ,skin and connective tissue diseases ,VDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Medical molecular biology: 711 ,Wnt Signaling Pathway ,[SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Multidisciplinary ,Carcinoma, Ductal, Breast ,Wnt signaling pathway ,Intracellular Signaling Peptides and Proteins ,Signal transducing adaptor protein ,LRP6 ,Cell Polarity ,[SDV.BDD.EO] Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis ,LRP5 ,Middle Aged ,Prognosis ,3. Good health ,Cell biology ,Female ,Cell Migration Assays ,DNA Copy Number Variations ,MAP Kinase Signaling System ,Science ,Blotting, Western ,Breast Neoplasms ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Article ,03 medical and health sciences ,Breast cancer ,Downregulation and upregulation ,Planar Polarity proteins ,Breast cacner ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Immunoprecipitation ,RNA, Messenger ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,Proportional Hazards Models ,Cell growth ,Membrane Proteins ,General Chemistry ,medicine.disease ,Carcinoma, Lobular ,Microscopy, Electron ,030104 developmental biology ,[SDV.BDD.EO]Life Sciences [q-bio]/Development Biology/Embryology and Organogenesis ,VDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Medisinsk molekylærbiologi: 711 ,Neoplasm Transplantation - Abstract
The non-canonical Wnt/planar cell polarity (Wnt/PCP) pathway plays a crucial role in embryonic development. Recent work has linked defects of this pathway to breast cancer aggressiveness and proposed Wnt/PCP signalling as a therapeutic target. Here we show that the archetypal Wnt/PCP protein VANGL2 is overexpressed in basal breast cancers, associated with poor prognosis and implicated in tumour growth. We identify the scaffold p62/SQSTM1 protein as a novel VANGL2-binding partner and show its key role in an evolutionarily conserved VANGL2–p62/SQSTM1–JNK pathway. This proliferative signalling cascade is upregulated in breast cancer patients with shorter survival and can be inactivated in patient-derived xenograft cells by inhibition of the JNK pathway or by disruption of the VANGL2–p62/SQSTM1 interaction. VANGL2–JNK signalling is thus a potential target for breast cancer therapy., Defects in non-canonical Wnt/planar cell polarity signalling have recently been linked to breast cancer aggressiveness. Puvirajesinghe et al. identify VANGL2, p62/SQSTM1 and JNK as important players in this pathway which may be amenable to therapeutic intervention in breast cancer.
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- 2016
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10. 0452 : MTOR inactivation during early postnatal development of mice myocardium leads to severe dilated cardiomyopathy due to altered translational efficiency and hypoxia-induced apoptosis
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Daniel Taillandier, Geneviève Derumeaux, Anne Sophie Nicot, Théophile Ohlmann, Dominique Baas, Geoffrey Texeira, Emilie Delaune, Lionel A. Tintignac, Laetitia Mazelin Bowyer, Baptiste Panthu, Edwige Belotti, Yann-Gaël Gangloff, Michel Ovize, Ging Zhang, Valerie Risson, Laurent Schaeffer, Oncovirology and Biotherapies, Lyon University, Contrôle traductionnel des ARNm eucaryotes et viraux – Translational control of Eukaryotic and Viral RNAs, Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Unité de Nutrition Humaine - Clermont Auvergne (UNH), Institut National de la Recherche Agronomique (INRA)-Université Clermont Auvergne (UCA), University of Basel (Unibas), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), and Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université-Institut National de la Recherche Agronomique (INRA)
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medicine.medical_specialty ,[SDV]Life Sciences [q-bio] ,mTORC1 ,030204 cardiovascular system & hematology ,mTORC2 ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,030212 general & internal medicine ,Mechanistic target of rapamycin ,PI3K/AKT/mTOR pathway ,ComputingMilieux_MISCELLANEOUS ,biology ,Cell growth ,business.industry ,RPTOR ,Hypoxia (medical) ,3. Good health ,Cell biology ,Endocrinology ,Knockout mouse ,biology.protein ,medicine.symptom ,business ,Cardiology and Cardiovascular Medicine - Abstract
Mechanistic target of rapamycin (mTOR) is a central regulator of cell growth, proliferation, survival and metabolism. mTOR inhibition is increasingly used in antitumoral therapies and mTOR inhibition with rapamycin was shown to be cardioprotective during aging and cardiac stress. Studies in genetic mice models have shown that mTOR is essential for heart development and cardiac function in adult. However, mTOR functions during postnatal cardiac development are not fully elucidated. We have therefore generated a cardiac-specific mTOR knockout mouse using α-MHC-Cre mice leading to mTOR inactivation in early postnatal mouse myocardium. The mutant mice develop a severe lethal dilated cardiomyopathy due to defects in cardiomyocyte growth, survival and subsequent fibrosis. In contrast to adult myocardium, both mTORC1 and mTORC2 activities are impaired in juvenile heart, as shown by hypophosphorylation of the translation inhibitor 4E-BP1 and loss of the cardioprotective AKTS473 phosphorylation. We find that translation initiation defects and altered ribosome biogenesis both contribute to impaired cardiomyocyte growth. In addition, we show that increased apoptosis is associated with activation of JNK kinase and p53 accumulation. Moreover mTORcmKO hearts display a strong decreased expression of the primary oxygen carrier, myoglobin, and HIF1α accumulation suggesting hypoxia. However, mTORcmKO hearts do not display HIF1 hypoxic response consistently with mTOR being essential for HIF1-dependant trancriptionnal activity. These observations indicate that hypoxia-induced apoptosis likely contribute to DCM in mTORcmKO mice. Altogether, our results demonstrate that mTOR is a key regulator of cardiomyocyte growth, viability and oxygen supply in early postnatal myocardium. Our findings highlight potential cardiotoxicity of new mTOR inhibitors and the importance to set up optimal treatments in cardiology to both target mTOR hypertrophic functions and maintain adequate oxygen supply.
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- 2015
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11. The Human PDZome: A Gateway to PSD95-Disc Large-Zonula Occludens (PDZ)-mediated Functions
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Frédérique Lembo, Jean-Claude Lissitzky, Marie-Josée Santoni, Nicolas Lenfant, Michael Sebbagh, Jérôme Reboul, Stephane Angers, Jolanta Polanowska, Michel Aurrand-Lions, Avais M. Daulat, Virginie Thomé, Stéphane Audebert, Akanksha Gangar, Mireille Montcouquiol, Karim Blibek, Laurent Kodjabachian, Shizue Omi, Jean-Paul Borg, Edwige Belotti, Centre de Recherche en Cancérologie de Marseille ( CRCM ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université ( AMU ), Centre d'Immunologie de Marseille - Luminy ( CIML ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Biologie du Développement de Marseille ( IBDM ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre de Recherches en Oncologie biologique et Oncopharmacologie ( CRO2 ), Aix Marseille Université ( AMU ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Physiopathologie du système nerveux central - Institut François Magendie, Université Bordeaux Segalen - Bordeaux 2-IFR8-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Department of biochemistry, Institute of Research in Immunology and Cancer, Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC), Centre de Recherche en Cancérologie de Marseille (CRCM), Aix Marseille Université (AMU)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Bordeaux Segalen - Bordeaux 2-IFR8-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Biochimie et Médecine Moléculaire [UdeM-Montréal], Université de Montréal (UdeM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), and Aix Marseille Université (AMU)-Collège de France (CdF)-Centre National de la Recherche Scientifique (CNRS)
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SCRIB ,SNX27 ,Embryo, Nonmammalian ,Proteome ,Xenopus ,PDZ domain ,Molecular Sequence Data ,PDZ Domains ,Enzyme-Linked Immunosorbent Assay ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Biology ,Biochemistry ,Fluorescence ,Analytical Chemistry ,Cell Line ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Cell Movement ,Two-Hybrid System Techniques ,Protein Interaction Mapping ,Morphogenesis ,Animals ,Humans ,Amino Acid Sequence ,Molecular Biology ,Peptide sequence ,Sorting Nexins ,030304 developmental biology ,0303 health sciences ,Binding Sites ,[ SDV.BC ] Life Sciences [q-bio]/Cellular Biology ,Tumor Suppressor Proteins ,Intracellular Signaling Peptides and Proteins ,Technological Innovation and Resources ,Membrane Proteins ,Reproducibility of Results ,Oncogene Proteins, Viral ,biology.organism_classification ,Cell biology ,Membrane protein ,Gene Knockdown Techniques ,Signal transduction ,Protein Kinases ,030217 neurology & neurosurgery - Abstract
International audience; Protein-protein interactions organize the localization, clustering, signal transduction, and degradation of cellular proteins and are therefore implicated in numerous biological functions. These interactions are mediated by specialized domains able to bind to modified or unmodified peptides present in binding partners. Among the most broadly distributed protein interaction domains, PSD95-disc large-zonula occludens (PDZ) domains are usually able to bind carboxy-terminal sequences of their partners. In an effort to accelerate the discovery of PDZ domain interactions, we have constructed an array displaying 96% of the human PDZ domains that is amenable to rapid two-hybrid screens in yeast. We have demonstrated that this array can efficiently identify interactions using carboxy-terminal sequences of PDZ domain binders such as the E6 oncoviral protein and protein kinases (PDGFRβ, BRSK2, PCTK1, ACVR2B, and HER4); this has been validated via mass spectrometry analysis. Taking advantage of this array, we show that PDZ domains of Scrib and SNX27 bind to the carboxy-terminal region of the planar cell polarity receptor Vangl2. We also have demonstrated the requirement of Scrib for the promigratory function of Vangl2 and described the morphogenetic function of SNX27 in the early Xenopus embryo. The resource presented here is thus adapted for the screen of PDZ interactors and, furthermore, should facilitate the understanding of PDZ-mediated functions.
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- 2013
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12. Primary cilium migration depends on G-protein signalling control of subapical cytoskeleton
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Jerome Ezan, Bernd Nürnberg, Nathalie Sans, Mireille Montcouquiol, Helen May-Simera, Edwige Belotti, André Le Bivic, Lutz Birnbaumer, Sandra Beer-Hammer, Léa Lasvaux, Jean-Paul Borg, Ana Novakovic, Anne-Catherine Lhoumeau, Aysegul Gezer, Physiopathologie du système nerveux central - Institut François Magendie, Université Bordeaux Segalen - Bordeaux 2-IFR8-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche en Cancérologie de Marseille (CRCM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes, Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Molecular and Cellular Neurobiology, Aix Marseille Université (AMU)-Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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Cell type ,Protein subunit ,Cell ,Cell Cycle Proteins ,Nerve Tissue Proteins ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,GTP-Binding Protein alpha Subunits, Gi-Go ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Cell Movement ,medicine ,Animals ,Cilia ,Cytoskeleton ,Cell Shape ,Protein Kinase C ,Adaptor Proteins, Signal Transducing ,030304 developmental biology ,0303 health sciences ,Hair Cells, Auditory, Inner ,biology ,Cilium ,Cell Polarity ,Cell Biology ,Kinocilium ,biology.organism_classification ,Phenotype ,Cell biology ,Hair Cells, Auditory, Outer ,medicine.anatomical_structure ,Gene Expression Regulation ,sense organs ,Drosophila melanogaster ,Carrier Proteins ,Cell Adhesion Molecules ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
International audience; In ciliated mammalian cells, the precise migration of the primary cilium at the apical surface of the cells, also referred to as translational polarity, defines planar cell polarity (PCP) in very early stages. Recent research has revealed a co-dependence between planar polarization of some cell types and cilium positioning at the surface of cells. This important role of the primary cilium in mammalian cells is in contrast with its absence from Drosophila melanogaster PCP establishment. Here, we show that deletion of GTP-binding protein alpha-i subunit 3 (Gαi3) and mammalian Partner of inscuteable (mPins) disrupts the migration of the kinocilium at the surface of cochlear hair cells and affects hair bundle orientation and shape. Inhibition of G-protein function in vitro leads to kinocilium migration defects, PCP phenotype and abnormal hair bundle morphology. We show that Gαi3/mPins are expressed in an apical and distal asymmetrical domain, which is opposite and complementary to an aPKC/Par-3/Par-6b expression domain, and non-overlapping with the core PCP protein Vangl2. Thus G-protein-dependent signalling controls the migration of the cilium cell autonomously, whereas core PCP signalling controls long-range tissue PCP.
- Published
- 2013
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13. Deregulation of the non‐canonical pathway in triple‐negative breast cancer
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Frédérique Lembo, Edwige Belotti, François Bertucci, Daniel Birnbaum, Emmanuelle Charafe-Jauffret, Jean-Paul Borg, and Avais M. Daulat
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Oncology ,Deregulation ,medicine.medical_specialty ,Non canonical ,business.industry ,Internal medicine ,Genetics ,Medicine ,business ,Molecular Biology ,Biochemistry ,Triple-negative breast cancer ,Biotechnology - Published
- 2013
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14. Protein tyrosine kinase 7 has a conserved role in Wnt/beta-catenin canonical signalling
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Anne Catherine Lhoumeau, Edwige Belotti, Sylvie Marchetto, Michael Sebbagh, Frédérique Lembo, Seung Taek Lee, Francesca Puppo, Akanksha Gangar, Jean-Paul Borg, Virginie Thomé, Marie Cibois, Laurent Kodjabachian, Thomas Prebet, Won Sik Shin, Patrick Lécine, Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Marseille (CRCM / U891 Inserm), Institut Paoli-Calmettes, and Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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MESH: Signal Transduction ,Embryo, Nonmammalian ,MESH: beta Catenin ,Xenopus Proteins ,Biochemistry ,MESH: Mice, Knockout ,Glycogen Synthase Kinase 3 ,Mice ,Xenopus laevis ,0302 clinical medicine ,GSK-3 ,MESH: Animals ,MESH: Organizers, Embryonic ,MESH: Xenopus Proteins ,beta Catenin ,ComputingMilieux_MISCELLANEOUS ,MESH: Glycogen Synthase Kinase 3 ,Mice, Knockout ,0303 health sciences ,Wnt signaling pathway ,LRP6 ,LRP5 ,Cell biology ,MESH: Wnt Proteins ,030220 oncology & carcinogenesis ,MESH: Cell Adhesion Molecules ,MESH: Receptor Protein-Tyrosine Kinases ,PTK7 ,Signal transduction ,Tyrosine kinase ,Signal Transduction ,[SDV.BC]Life Sciences [q-bio]/Cellular Biology ,Biology ,MESH: Two-Hybrid System Techniques ,03 medical and health sciences ,MESH: Xenopus laevis ,Two-Hybrid System Techniques ,MESH: Homeodomain Proteins ,Genetics ,Animals ,Humans ,Molecular Biology ,MESH: Mice ,030304 developmental biology ,Homeodomain Proteins ,MESH: Humans ,Scientific Reports ,Organizers, Embryonic ,MESH: Embryo, Mammalian ,Receptor Protein-Tyrosine Kinases ,MESH: Embryo, Nonmammalian ,Embryo, Mammalian ,Molecular biology ,Wnt Proteins ,Catenin ,Cell Adhesion Molecules - Abstract
International audience; The receptor protein tyrosine kinase 7 (PTK7) was recently shown to participate in noncanonical Wnt/planar cell polarity signalling during mouse and frog embryonic development. In this study, we report that PTK7 interacts with β-catenin in a yeast two-hybrid assay and mammalian cells. PTK7-deficient cells exhibit weakened β-catenin/T-cell factor transcriptional activity on Wnt3a stimulation. Furthermore, Xenopus PTK7 is required for the formation of Spemann's organizer and for Siamois promoter activation, events that require β-catenin transcriptional activity. Using epistatic assays, we demonstrate that PTK7 functions upstream from glycogen synthase kinase 3. Taken together, our data reveal a new and conserved role for PTK7 in the Wnt canonical signalling pathway.
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- 2011
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